The proposed experiments will examine mechanisms by which central beta-1 adrenergic receptors are involved in the mediation of antidepressant activity. Based on the results of previous work, four specific hypotheses are proposed. First, it is hypothesized that beta-1 adrenergic receptors are important mediators of antidepressant-like effects observed in behavioral models. Second, it is hypothesized that repeated treatment with antidepressants, particularly those that directly affect noradrenergic systems, results in sustained or enhanced stimulation of central beta-1 adrenergic receptors. Third, it is hypothesized that alpha-1 adrenergic receptor stimulation and Type 4 phosphodiesterase (PDE4) inhibition potentiate antidepressant-like behavioral effects mediated by beta-1 adrenergic receptors. Fourth, it is hypothesized that antidepressant-like behavioral effects mediated by central beta-1 adrenergic receptors are resistant to tolerance development. These hypotheses will be tested using two behavioral models. Discrimination of centrally administered isoproterenol will provide an index for assessing stimulation of central beta-1 adrenergic receptors in vivo. Behavior maintained under a differential-reinforcement-of-low-rate (DRL) schedule will be used to assess antidepressant-like behavioral effects. First, the ability of antidepressants from different pharmacological classes to substitute for the discriminative stimulus effects of centrally administered isoproterenol will be determined. Second, this behavioral model will be used to assess the functional state of noradrenergic neurons/beta-1 adrenergic receptors following repeated treatment with antidepressants. Third, the manner by which alpha-1 adrenergic receptor stimulation and PDE4 inhibition alters the antidepressant-like effects on DRL behavior resulting from beta-1 adrenergic receptor stimulation will be examined. Fourth, the persistence of antidepressant-like behavioral effects mediated by beta-1 adrenergic receptors will be assessed. The results of the proposed experiments will elucidate mechanisms mediating antidepressant effects associated with central beta-1 adrenergic receptors and will begin to identify receptor and post-receptor mechanisms that can be targeted pharmacologically to produce or augment antidepressant activity.